(1). Field of the Invention
The present invention provides novel compounds having pharmaceutical activity which are useful as pharmaceutical agents and, more particularly, as analgesic agents for the treatment of pain in animals, pharmaceutical compositions containing one or more of these compounds, methods of use employing these compounds and methods of manufacturing these compounds.
More specifically, the present invention concerns: (1) substituted tyrosyl diamide compounds which, by apparently acting as neurotransmitters or neuromodulators in the central nervous pain-suppressant system, induce analgesia in animals; (2) pharmaceutical compositions containing one or more of these compounds in combination with a pharmaceutically-acceptable carrier; and (3) methods of treating pain employing these compounds.
Analgesic compounds are agents which alleviate pain without causing a loss of consciousness and, thus, which are useful for treating pain and, often, for reducing inflammation.
The major classes of analgesic compounds include analgesic-antipyretic compounds, which are compounds which alleviate pain and/or reduce fever, such as salicylates, and narcotic analgesics, or opiates, compounds which alleviate pain and/or induce sleep.
While salicylate and salicylate-like agents (non-steroidal antiinflammatory agents or NSAIDS) are efficacious in relieving pain, they often exhibit undesirable side effects, such as gastrointestinal irritation, including bleeding, as with aspirin, allergic response, as with aspirin, and/or liver toxicity with extended use, as with acetaminophen.
The compounds of the present invention are not salicylates, and represent another class of compounds which are useful as analgesic agents.
(2). Description of the Related Art
Opioids are a class of drugs which are, to varying degrees, opium-like or morphine-like in their properties. Although opioids are employed therapeutically primarily as analgesics, they have many other pharmacological effects as well, and they have some of the properties of certain naturally-occurring peptides.
By the year 1967, researchers working in the art had concluded that the complex interactions in the body between morphine agonists (morphine-like drugs) and mixed morphine agonist-antagonists could best be explained by postulating the existence of more than one type of cellular receptor for the opioids, and for related drugs.
Subsequent research in the area revealed that multiple categories of opioid receptors exist and, further, that there are at least three distinct families of naturally-occurring opioid peptides: (1) the endorphins; (2) the enkephalins; and (3) the dynorphins.
Although studies concerning the binding of opioid drugs and peptides to specific sites in the brain, and in other organs, have suggested the existence of, perhaps, as many as eight different types of opioid receptors in the body, there is reasonably firm evidence to support the conclusion that three major categories of opioid receptors, designated .mu., .kappa. and .delta., exist in the central nervous system. The classical opioid antagonist, naloxone, has been found to bind with high affinity to all three categories of opioid receptors.
The multiplicity of opioid receptor types in the central nervous system is now well established. Though much work has been directed at defining the structural elements that determine receptor specificity and efficacy, these factors are still, at best, poorly understood.
The rigid alkaloid opiates, typified by morphine, are generally believed to produce analgesia by interacting with the .mu. receptor.
It is now well established that the .delta. opioid receptor type mediates analgesia in the mouse, and that this site is generally associated with fewer gastrointestinal transit effects, and with less physical dependence, than the .mu. opioid receptor type.
In 1975, Hughes and Kosterlitz described the isolation of two naturally-occurring pentapeptides, "methionine enkephalin" (H.sub.2 N-Tyr-Gly-Gly-Phe-Met-OH) and "leucine enkephalin" (H.sub.2 N-Tyr-Gly-Gly-Phe-Leu-OH), from the brain. These pentapeptides occur in nerve endings of brain tissue, spinal cord and the gastrointestinal tract, bind to the same receptor sites as do the opiates, and exhibit some weak morphine-like actions, actions which were antagonized by naloxone.
That same year, Goldstein and his colleagues reported the presence of peptide-like substances in the pituitary gland which exhibited opioid activity.
The naturally-occurring pentapeptides isolated by Hughes and Kosterlitz appear to act as neurotransmitters or neuromodulators in the central nervous system, and bind stereospecifically to partially-purified brain opioid receptor sites. See, for example, Bradbury et al., Nature, 260, 793 (1976). These natural peptides are also highly active in bioassays for opioid activity, but exhibit only weak, fleeting analgesic activity when injected directly into the brain of the rat, and exhibit no activity when administered systemically in the rodent. See, for example, Belluzzi, et al., Nature, 260, 625 (1976).
In an attempt to overcome the lack of in vivo activity of the naturally-occurring pentapeptides isolated by Hughes and Kosterlitz, investigators working in the art have made numerous modifications to these enkephalins.
Among the modifications made to methionine enkephalin has been the synthesis of short-Chain, enkephalin-like peptides, among them dipeptide and tripeptide alkylamides, as described by Kiso et al., "Peptide Chemistry 1981," Protein Research Foundation, Osaka, Japan, 65-70 (1982).
Vavrek et al., Peptides, 2, 303 (1981), disclose analogs of the enkephalins, including the dipeptide, tyrosine-D-alanine-phenylpropylamide.
The large-scale use of synthetic enkephalins has been impractical due to various difficulties. One of the difficulties associated with natural enkephalins is that they are extremely unstable, and their half-lives in the blood are extremely short.
Attempts at solving these problems have focused upon altering the structure of the enkephalin molecule. Alterations in the enkephalin structure produce different pharmacological effects. To some degree, these effects are due to differential interactions with the various opioid receptors. However, it has been difficult to study the role of each receptor type, or to induce selectively the pharmacological and therapeutic effects associated with each receptor type, because the enkephalin analogs, to date, have had a high degree of selectivity for only the mu (.mu.), rather than for the delta (.delta.), opioid receptors.
For several years, the prototypic agonist for the .delta. opioid receptor has been the cyclic enkephalin analog [D-Pen.sup.2, D-Pen.sup.5 ]enkephalin. The recently-discovered deltorphins, heptapeptides of frog skin origin, are also highly selective and potent, in vitro, at this receptor. However, the relatively large size of these peptides suggest potential problems in crossing the blood brain barrier to elicit analgesia after systemic administration, a desirable property for a useful opioid analgesic. This has also hampered attempts to more fully define the functional role of .delta. receptors in the central nervous system.
Compounds within the present invention are tyrosyl diamide opioid agonists which have a substantial affinity for both the .mu. and the .delta. opioid receptors, and which produce analgesia following central and peripheral routes of administration in animals.
The compounds of the present invention are structurally distinct from that which has been described in the art.
Moreover, compounds of the present invention exhibit unexpected and surprisingly superior analgesic activity when compared to compounds of the prior art. These novel tyrosyl diamide compounds show improved potency and bioavailability as analgesic agents by central and peripheral routes of administration, such as by subcutaneous administration.
A. R. Jacobson et al., in "Minimum-Structure Enkephalin Analogues Incorporating L-Tyrosine, D (or L)-Phenylalanine, and a Diamine Spacer," J Med Chem., 32, 1708-1717 (1989), disclose a series of compounds in which L-tyrosine was linked to N-acyl phenylalanine through a variety of diamine spacers. Tyrosyl diamide compounds within the present invention were found to be surprisingly and unexpectedly superior to the peptide compounds described by Jacobson et al., as will be discussed in more detail hereinbelow.